An inverse association between physical activity and risk for breast cancer has been proposed and available evidence indicates that protection against cancer is due to effects of physical activity that are distinct from as well as related to its effects on adult weight gain. Little is know about how physical activity per se affects the risk for cancer. Given current trends towards reduced occupational activity, most women will need to use recreational activity to experience health benefits. This subset of physical activity is generally referred to as exercise. In this application we propose to study the influence of three principal components of exercise, its intensity, duration, and frequency, on the development of breast cancer in a widely used experimental model system. Our objectives are described in the following aims: 1) Determine the exercise intensity, duration, and frequency that inhibits the post initiation stage of mammary carcinogenesis. For those individuals who are maintaining body weight in an acceptable range for cancer risk reduction, but who also wish to exercise for further reduction in risk, the relative importance of exercise intensity, duration and frequency for cancer prevention is unclear and requires investigation. A newly developed model for exercise in which running behavior is maintained by food reinforcement will be used for this work. This approach not only circumvents the use of adverse stimuli to maintain compliance to an exercise protocol, but also permits manipulation of the ratio of dietary energy ingested relative to the amount of energy expended during exercise. 2) Investigate the effects of exercise per the conditions described in Aim 1 on insulin-like growth factor (IGF) and corticosterone and a signaling pathway they may affect in mammary tissue and in pre-malignant and malignant mammary pathologies. We hypothesize that the effects of exercise on insulin-like growth factor (IGF) and corticosterone are likely to account, at least in part, for inhibitory activity. Therefore, the proposed experiments will focus on the investigation of these molecules. 3) Evaluate whether exercise-related alterations in cell proliferation, apoptosis and/or angiogenesis are likely to account for cancer inhibitory activity. Based on those results and findings from Aim 2, investigate the molecular pathway(s) most likely to account for the cancer inhibitory activity of exercise. Little information exists concerning the effects of exercise on the misregulation of cellular processes involved in carcinogenesis. For the cellular process (proliferation, apoptosis or angiogenesis) identified, molecular studies will be conducted. The preclinical experiments proposed should provide critical information concerning the effects of exercise on biomarkers and mechanisms in relation to cancer endpoints. These data should facilitate the translation of pre-clinical and clinical research to public health recommendations for cancer risk reduction.